Crizotinib Extends Survival Versus Chemotherapy in Advanced NSCLC

Phoebe Starr

Uncategorized

The PROFILE 1007 trial, reported at the 2012 ESMO Congress, showed positive results for a targeted therapy in patients whose tumors expressed that target. The first-in-class ALK inhibitor crizotinib prolonged progression-free survival (PFS) and improved response rates compared with single-agent chemotherapy in patients with advanced, previously treated, ALK-positive (ALK+), non–small cell lung cancer (NSCLC). Patients treated with crizotinib had greater improvement in lung cancer symptoms and quality of life (QOL) compared with patients receiving chemotherapy. PROFILE 1007 is the first trial to compare crizotinib head-to-head with chemotherapy in ALK+ NSCLC.

ALK rearrangements are found in about 5% of lung cancers. Even though this is a small percentage, lung cancer is so prevalent that ALK positivity accounts for about 50,000 new cases each year. Studies show that younger patients, those who never smoked, and adenocarcinoma cases are more likely to be ALK+.

“These results establish crizotinib as the standard of care for patients with advanced previously treated ALK+ NSCLC,� stated lead author Alice Shaw, MD, Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, Massachusetts. Crizotinib is approved for the treatment of ALK+ NSCLC in the United States.

The international PROFILE 1007 trial randomized 347 patients with ALK+, stage IIIb or IV NSCLC to crizotinib 250 mg bid, pemetrexed 500 mg/m², or
do­cetaxel 75 mg/m² on a 21-day cycle. Patients treated with crizotinib received a median of 11 cycles, while those treated with chemotherapy received a median of 4 cycles.

For the primary end point, median PFS was 7.7 months with crizotinib versus 3 months with chemotherapy, reducing the risk of progression by 51% with crizotinib (P<.0001). Median PFS was 7.7 months with crizotinib versus 4.2 months with pemetrexed (P=.0004) and 2.6 months with docetaxel (P<.0001).

Overall response rate was tripled in the crizotinib group: 65.3% versus 19.3% for single-agent chemotherapy (P<.0001).

No overall survival (OS) benefit was seen with crizotinib in an interim analysis. However, longer follow-up is needed so the data can mature, Shaw said. OS will likely be confounded by crossover, she said, since patients were allowed to cross over to crizotinib if progression occurred.

Adverse events associated with crizotinib were mild and manageable in the study. The rate of toxicities grade 3 or higher was under 5% for most toxicities; in the crizotinib arm, elevated transaminases were reported in 16% of patients and pulmonary embolism in 5%. Myelosuppression was more frequent in the chemotherapy arms compared with crizotinib.

Patient-reported outcomes suggested that QOL was superior on crizotinib compared with chemotherapy. Time to deterioration in lung cancer symptoms was a median of 5.6 months with crizotinib versus 1.4 months with chemotherapy (P<.0001).

As with other targeted therapies, patients with advanced cancers will develop resistance to crizotinib. Investigational drugs such as LBK 178, AB6 273, and heat shock protein inhibitors may be able to overcome resis­tance that develops with crizotinib.

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